Despite the high prevalence and problems associated with cannabis related disorders (CRDs), we lack effective medications and research is nascent. Drug discrimination (DD) has been used to evaluate medications for treating substance use disorders other than CRDs. Only one human study of marijuana DD has been conducted, and none have tested the effects of a medication on marijuana discrimination. Strengths of the DD model include being valid, reliable, sensitive, selective, and accommodating subjective and physiological measures. Drug choice procedures offer another valid approach for testing CRD medications. The Multiple Choice Procedure (MCP) can efficiently assess the reinforcing effects of a drug relative to an alternative (e.g. money). Medications should shift choice from marijuana to non-drug reinforcers. Only one MCP study of marijuana has been conducted with humans;none have tested the effect of a medication on marijuana reinforcement with this index. Thus, DD and MCP methods have distinct benefits and they are compatible, but their advantages have not yet been exploited in CRD medication development. This project will develop and test the sensitivity and selectivity of a smoked marijuana combined DD/choice paradigm in humans, enabling us to link the discriminative stimulus, subjective and relative reinforcing efficacy of marijuana, and the extent to which these are attenuated by medications. The long-term goal is to show this combined model is a time-efficient, cost-effective and comprehensive screen of putative CRD medications. Short-term goals of this proof-of-concept study are as follows. Participants will be trained to discriminate the effects of smoked marijuana. Dose-response functions will then be generated with marijuana doses different than the training dose to test the model's sensitivity, and generalization tests will be conducted with drugs that are pharmacologically similar to marijuana (oral THC) and different (d-amphetamine) to determine the model's selectivity. Next, the ability of oral THC to attenuate the subjective, physiological, reinforcing, and discriminative stimulus effects of smoked marijuana will be determined. The central hypothesis of this application is that the combined DD/MCP model will be a sensitive and selective paradigm that can detect a medication "signal" (i.e. attenuation of one or more effects in the array of measures) that would suggest promise for development. Specific aims are to determine whether: (1) smoked marijuana occasions a dose-dependent increase in marijuana-appropriate responding (DD sensitivity) and (2) reinforcing effects (MCP);(3) oral THC and (4) d-amphetamine occasion marijuana-appropriate responding (DD selectivity);oral THC dose- dependently attenuates the (5) discriminative stimulus and (6) reinforcing effects of smoked marijuana. We will explore relations among marijuana's discriminative stimulus, reinforcing, subjective (e.g. craving) and physiological effects, and the relative ability of oral THC to block these effects. The proposed work is highly innovative in combining two existing paradigms (DD, MCP) to aid medication development for a drug class that has not yet been studied in controlled laboratory studies. This model has scientific and health significance for its potential to rapidly and comprehensively screen, and thus identify, promising compounds for CRDs prior to undertaking expensive and time-consuming clinical trials. PUBLIC HEALTH RELEVANCE: Despite the high prevalence of marijuana abuse and dependence, there are no medications available to treat these important disorders and research on the development of pharmacological treatments is in its infancy. As clinical trials are both expensive and time-consuming, it would be advantageous to have a controlled and validated laboratory model to screen new compounds and thus identify the most promising medications that warrant further testing. The current application proposes to develop and utilize a marijuana drug discrimination/marijuana self-administration paradigm in humans that would provide an efficient and cost-effective method for evaluating pharmacological compounds, as well as a strategy for testing pharmacologic treatments in combination with evidence- based interventions (i.e., behavioral treatments), which together might have the greatest potential to lead to integrative and successful treatment for cannabis related disorders.